Tamper Resistant Dosage Form Composition And Process Of Making The Same

ABSTRACT

A tamper-resistant dosage form including a therapeutic agent-substrate complex embedded in a thermo-formable matrix; such that the complex includes at least one therapeutic agent bound to at least one substrate to form the therapeutic agent-substrate complex. The at least one substrate is being selected from the group consisting of a polyelectrolyte, an organic counter-ion, a pharmacologically inert organic component of a prodrug, an inclusion compound and an inorganic adsorbent; and the thermo-formable matrix includes one or more thermoplastic polymers and optionally at least one pharmaceutical additive.

CROSS REFERENCE TO RELATED APPLICATION

This application is based on, and claims the benefit of U.S. ProvisionalPatent Application No. 61/959,830, filed Sep. 3, 2013, and U.S. Ser. No.14/157,658 which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to an improved pharmaceutical dosage form.More particularly, the invention relates to a tamper-resistant dosageform including a therapeutic agent-substrate complex and athermo-formable matrix comprising at least one thermoplastic polymer andone or more pharmaceutical additives, and the method of making same.

BACKGROUND OF INVENTION

Product tampering occurs when a dosage form is manipulated to achieve anobjective in ways that is not intended per dosing instructions. It mayinvolve drug abusers who tamper with the dosage form to obtain euphoria,or non-abusers such as patients and caregivers who innocently tamperwith the dosage form to address legitimate concerns. For example, anelderly patient may break a dosage form to facilitate swallowing or acaregiver may break a dosage form to reduce the therapeutic dose.

Prescription medications are being abused at an alarming rate. The mostcommonly abused classes of prescription drug products are opioids(narcotics), sedatives/hypnotics, stimulants, and tranquilizers. Themost commonly abused over-the-counter drugs are decongestants,antihistamines and cough medicines. An estimated 52 million people haveused prescription drugs for nonmedical reasons at least once in theirlifetimes.

Particularly, abuse of prescription painkillers is a growing, publichealth problem that has been steadily worsening as reflected inincreased treatment admissions, emergency room visits, and overdosedeaths. About 164 million patients/year visit the doctor office for painof which 20% receive opiate prescriptions for pain treatment. Number ofopiate prescriptions has been steadily increasing since 1991. In 2013alone, 230 million opioid prescriptions were dispensed. The painmanagement market generated $7.3 billion in US sales in 2012. The marketis predicted to increase to $9.8 billion by 2018 and to $11.3 billion by2023.

In 2010, more than 40% of all drug poisoning deaths involved opioidanalgesics, and the number of overdose deaths involving opioidanalgesics has more than tripled since 1999. The CDC's latest figuresshow that 16,500 people died from overdoses tied to common narcotic painrelievers in 2010. Over dosage of opiates occurs due to intentional orunintentional tampering of opiate drug products. Abusers tamper withdosage form to obtain euphoria, while patients/caregivers manipulatedosage forms to facilitate dosing. Pain relievers, such as OxyContin®and Vicodin®; anti-depressants, such as Xanax® and Valium®, andstimulants, such as Concerta®, Adderall®, are the most commonly abusedprescription drugs.

While drug abuse has been common with all dosage forms, modified releaseproducts have been particularly attractive to drug abusers due to thehigh drug content in the dosage forms. When these dosage forms aretampered with or altered, they may lead to more rapid release of thetherapeutic agent, which in turn may provide the drug_abusers withgreater euphoria that they desperately desire.

To address the drug abuse epidemic, pharmaceutical companies havestarted to develop abuse deterrent formulations, and the FDA has alsoissued a guideline to encourage development of more effectivetamper-resistant formulations. Abuse deterrent formulations are designedto thwart deliberate attempts by drug-abusers to extract the activeingredient or blunt the euphoric effects from unapproved methods ofadministration.

Common methods of drug abuse include: (1) oral ingestion, where thedosage form is chewed, to destroy the release controlling matrix anddeliver high doses of therapeutic agent into the gastrointestinal tract,and swallowed, with or without co-ingestion of alcohol; (2) intravenousinjection, which involves extraction of the therapeutic agent from thedosage form using an appropriate solvent, followed by injection of thetherapeutic agent directly into the blood stream; (3) nasal snorting,where the dosage form is crushed, milled, or ground into a fine powderand administered intra-nasally to facilitate rapid drug absorptionthrough the lining of the nasal passages; and (4) smoking, where thetherapeutic agent is vaporized for inhalation by subjecting the dosageform to heat.

In addition, dosage forms, particularly modified release dosage forms,are relatively large in size and may pose a dosing challenge to manypeople including the elderly and young. Often, patients and caregiversmay break the dosage form to reduce the size. By doing so, theyinadvertently compromise the release controlling mechanism of the dosageform and potentially lead to dose dumping, often with adverseconsequences.

To circumvent dosage form tampering, many tamper resistant formulationshave been described.

U.S. Pat. No. 7,510,726 describes a therapeutic pharmaceuticalcomposition comprising a mixture consisting of at least one opioidanalgesic, gel forming polyethylene oxide, and at least onedisintegrant. Due to the physical properties of the gel forming polymer,the extended release properties of the disclosed dosage form is expectedto be compromised upon mastication and not prevent abuse by chewing andswallowing.

U.S. Pat. No. 7,771,707 describes a solid abuse deterrent pharmaceuticalcomposition of a pharmaceutically active agent prone to abuse, and oneor more fatty acids or fatty amines present in molar excess relative tothe pharmaceutically active agent. As taught, the fatty acids and fattyacid amines which impart lipophilicity on the drug substance may besusceptible to physical instability.

U.S. Pat. No. 7,776,314 describes parenteral abuse-proofed solid dosageform for oral administration, comprising one or more active ingredientswith potential for abuse, and at least one viscosity-increasing agent.Invention deters only abuse by injection.

U.S. Pat. No. 8,075,872 describes an abuse resistant dosage formthermoformed by extrusion and having a breaking strength of at least 500N, which contains a mixture of one or more active ingredients with abusepotential, polyalkylene oxides, physiologically acceptable auxiliarysubstances, and optionally wax and cellulosic derivatives. The discloseddosage form contains low t_(g) hydrophilic polymers that may notwithstand mastication when exposed to saliva due to plasticization.

U.S. Pat. No. 8,409,616 describes a therapeutic pharmaceuticalcomposition comprising a water-soluble drug susceptible to abuse, a gelforming polymer and a disintegrant. As taught, the gel forming polymersbased on polyethylene oxide are susceptible to chewing and masticationupon contact with saliva.

U.S. Pat. No. 8,449,909 describes a therapeutically effectivepharmaceutical composition comprising solid microparticles, wherein themicroparticles comprise an active agent, one or more fatty acids, andone or more carrier materials selected from waxes or wax-likesubstances. The fatty acids and fatty acid amines as taught, impartlipophilicity on the drug substance but may not ensure physicalstability upon storage. U.S. Patent Application Publication 2008/0075770describes a monolithic solidified oral dosage form prepared by a thermalprocess comprising a therapeutic agent and a hydrophilic polymer. Thedisclosed drug molecules incorporated in a hydrophilic polymeric matrixhave a tendency to diffuse when mobility of the polymer is increased dueto solvent or temperature effect, thereby increasing extractability.

U.S. Pat. No. 8,486,448 describes a controlled release formulationcomprising a core comprising a superabsorbent material, a controlledrelease coat surrounding the core; and a plurality of controlled releasemicroparticles containing a pharmaceutically active agent. This abusedeterrent relies on a hard coating that may be susceptible to extractionby both aqueous and organic solvents.

U.S. Pat. No. 8,202,542 describes an abuse resistant opioid drug-ionexchange resin complexes having hybrid coatings containing a curedpolyvinylacetate polymer and a pH-dependent enteric coating layer mixedtherein. As taught, these polymer coatings are soluble in aqueous ororganic solvents which would make the dosage form susceptible abuse byextraction.

U.S. Patent Application Publication 2011/0020451 describes atamper-resistant thermoformed pharmaceutical dosage form having abreaking strength of at least 300 N and comprising an opioid, aphysiologically acceptable acid and a polyalkylene oxide. The discloseddosage form is expected to be susceptible to abuse by chewing andswallowing.

U.S. Patent Application Publication 2012/0148672 describes a coatedmodified release opioid-ion exchange resin complex comprising apharmaceutically effective amount of an opioid bound to apharmaceutically acceptable ion exchange resin complex; and apH-independent, high tensile strength, water permeable, water insoluble,diffusion barrier coating. As disclosed, the coating is expected todissolve in organic solvents and high aqueous pH, which would make thedosage form reduce extraction by the complexing ion exchange resin only.

As a result, in spite of the various tamper-resistant formulationapproaches mentioned above, there is still a need for improved abusedeterrent formulations that better prevent common methods of dosage formtampering and associated drug abuse administration routes with orwithout the incorporation of aversive agents and agonist/antagonists inthe dosage form.

In contrast, the present invention eliminates or reduces all forms oftampering, and hence all modes of abuse. The invention relates to anerodible dosage form that has a dry core which hydrates on the surfaceupon exposure to extraction fluid to form a thin gel layer that limitswater penetration into the core. The dosage form also has a synchronizedbarrier system that provides it with plasticity and hardness whichrenders the dosage form resistant to chewing, crashing and grinding, andvolatilization.

SUMMARY OF THE INVENTION

According to one embodiment, the present invention is related to atamper-resistant dosage form comprising of a therapeutic agent-substratecomplex embedded in an erodible thermo-formable matrix, wherein thetherapeutic agent-substrate complex is prepared by an extrusion process,and the therapeutic agent-substrate complex is embedded in an erodiblethermo-formable matrix by a granulation process. The ratio of thetherapeutic agent to the substrate in the complex is from 1:20 to 20:1by weight, while the ratio between the therapeutic agent-substratecomplex to the erodible thermo-formable matrix is from 1:10 to 10:1 alsoby weight. Optionally, a free therapeutic agent or a substrate isembedded in the erodible thermo-formable matrix along with thetherapeutic agent-substrate complex.

Alternatively, a prodrug, which is comprised of a covalently bonded drugwith an organic moiety, is embedded in the erodible thermo-formablematrix in place of the therapeutic agent-substrate complex.

The erodible thermo-formable matrix comprises at least one cellulosicthermoplastic polymer and optionally at least one non-cellulosicthermoplastic polymer and at least one pharmaceutical additive, whereinthe amount of the pharmaceutical additive in the matrix is less than 20%by weight.

The tamper-resistant dosage form is comprised of tablets andmultiparticulates wherein tampering is reduced or eliminated through asynchronized barrier mechanism; wherein the detrimental effects ofoverdosing is minimized or eliminated through the interaction betweenthe dosage form and the contents of the gastrointestinal fluid whichlimits drug availability for absorption; wherein the dosage formscomprise template formulations where one therapeutic agent issubstituted for another in a given formulation without altering thedissolution profiles or tamper-resistant properties of the dosage form;wherein the chemical and physical stability of the therapeutic agent andthe physical stability of the dosage form is assured

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic drug release mechanism of tamper resistantdosage forms.

FIG. 2 a shows extraction of Coffee grinder milled tablets after 15minutes.

FIG. 2 b shows extraction of Coffee grinder milled tablets after 60minutes.

FIG. 3 shows dissolution profiles of tamper resistant tablets.

FIG. 4 shows dissolution profiles of three different therapeutic agentsin the same template tamper resistant tablet formulation.

FIG. 5 shows dissolution profiles of tamper resistant multiparticulatescompressed in tablets.

DETAILED DESCRIPTION OF THE INVENTION

An embodiment of the invention is an erodible tamper-resistant dosageform that is resistant to various tampering modes. The tamper-resistantdosage form comprises a therapeutic agent-substrate complex embedded ina thermo-formable matrix. It has been discovered that a therapeuticagent-substrate complex embedded into a thermo-formable matrix iseffective against all forms of product tampering and drug abuse withoutthe use of aversion agents and antagonists. A complex of the therapeuticagent and a substrate is formed first prior to incorporation into thethermo-formable matrix in order for the formulation to providetamper-resistance. While pre-formation of the complex is preferred foroptimal performance, in some cases, particularly with inorganicadditives, the drug-substrate association could occur in situ duringprocessing. Alternatively, a prodrug, which is comprised of a covalentlybonded drug with an organic moiety, is embedded in the erodiblethermo-formable matrix in place of the therapeutic agent-substratecomplex.

According to the disclosure, a “therapeutic agent” means a substancethat elicits a pharmacologic response when administered by a patient ordrug abuser. “Therapeutic agent” and “drug” are used interchangeably.“Substrate” means a substance that interacts with the therapeutic agentto form a complex. “Complex” means a chemical association of a drugsubstance with a substrate through ionic bonds, polar covalent bonds,covalent bonds, and hydrogen bonds. A “prodrug” is substance thatconverts into an active form through enzymatic cleavage when ingested,and considered a complex according to the disclosure. A “pharmaceuticaladditive” is a substance that is added to formulations to improvefunctionality and processability of the dosage forms. A “thermoplastic”polymer is a polymer that is solid at room temperature, and becomespliable and moldable at elevated temperatures. “Tampering” means anintentional or an unintentional manipulation of dosage forms in a mannerthat is not intended for by dosing instructions, such as by chewing,crushing, grinding, extraction and volatilization.

Preparation of the Therapeutic Agent-Substrate Complex:

The therapeutic agent-substrate complex is prepared using a novelreactive extrusion process. The process is fast and continuous and moreefficient compared to other commonly used processes. It allows thecomplexation process to proceed at a faster rate by providingflexibility in processing temperatures and online incorporation of pHmodifiers and other additives that promote complex formation. As aresult, the process has greater than 95% efficiency in the degree ofcomplexation, a factor that is critical when considering the high costof therapeutic agents. The extruder, which behaves as a reactor, ispreferably a twin screw extruder. It comprises uniquely assembledconveying and mixing elements, and temperature controlled modularbarrels that constitute a continuous reaction vessel. Along the extruderlength, one or more liquid injection and powder feed ports are insertedin the barrels, wherein the number and location of the ports aredictated by the complexation process requirements.

During the complexation process, the drug and substrate are pre-blendedand the blend introduced into the extruder through a powder feed port.At a second port downstream from the first feed port, an aqueous liquidis added at a controlled rate to generate a heavy suspension. Thesuspension is collected, dried in a drying oven and stored for furtherprocessing.

The ratio of the therapeutic agent to the substrate in the complex isfrom 1:50 to 50:1 by weight, preferably 1:20 to 20:1 and morepreferably, from 1:10 to 10:1. The average particle size distribution ofthe substrate is less than 500 u (micron), preferably less than 250 uand more preferably, less than 75 u.

Alternatively, the complex may be prepared by a variety of processesknown in the art.

Embedding Therapeutic Agent-Substrate Complex within Thermo FormableMatrix:

The therapeutic agent-substrate complex is blended with at least onecellulosic thermoplastic polymer and optionally at least onenon-cellulosic thermoplastic polymer, or at least one pharmaceuticaladditive, or both, and the blend melt granulated at processingtemperatures of less than 175° C. and preferably less than 150° C. usinga twin-screw extruder. Alternatively, a blend of the thermoplasticpolymers and optionally at least one pharmaceutical additive is fed intothe extruder through the first powder feed port and allowed to meltbefore the therapeutic agent-substrate complex is introduced through asecond powder feed port downstream from the first feed port and mixedwith the molten mass in the extruder. In both procedures, the meltgranulated material or extrudate is shaped downstream to providetamper-resistant tablets or multiparticulates that are filled intocapsules or compressed into tablets. The ratio of the therapeuticagent-substrate complex to the thermo-formable matrix varies, by weight,from 1:20 to 20:1, and preferably from 1:10 to 10:1, and more preferablyfrom 1:5: to 5:1.

The tamper-resistant dosage form of the present invention can beprepared according to the steps of:

(1) Blending at least one therapeutic agent and at least one substratein a drug-to-substrate ratio from between 1:20 to 20:1 by weight;

(2) Reacting the at least one therapeutic agent and the at least onesubstrate to form a therapeutic agent-substrate complex using a reactiveextrusion process;

(3) Forming a thermo-formable matrix blend with at least one cellulosicthermoplastic polymer and optionally at least one non-cellulosicthermoplastic polymer, and at least one pharmaceutical additive;

(4) Mixing the therapeutic agent-substrate complex and thethermo-formable matrix blend in a ratio from between 1:10 to 10:1;

(5) Granulating the therapeutic agent-substrate complex and thethermo-formable matrix blend to form the tamper-resistant dosage form inwhich the therapeutic agent-substrate complex is embedded in thethermo-formable matrix; and

(6) Shaping the tamper-resistant dosage form into one of tablet form andmultiparticulate form.

The granulating step of (5) can be carried out by a hot melt extrusionprocess, or optionally by a wet granulation process or a dry granulationprocess.

The thermo-formable matrix imparts plasticity and hardness to the dosageform. Embedding the drug-substrate complex in the thermo-formable matrixproduces a synergistic effect that renders the dosage form moreresistant to tampering while releasing the therapeutic agent in acontrolled manner. If only the therapeutic agent-substrate is usedwithout the thermo-formable matrix during the preparation of extendedrelease dosage forms, or if the therapeutic agent is dispersed in thethermo-formable matrix without a substrate, or if only a blend of thetherapeutic agent and the substrate but not a complex is dispersed inthe thermo-formable matrix the formulations do not exhibit bothtamper-resistant and extended release properties.

According to the disclosure, cellulosic thermoplastic polymers comprise,but not limited to, hydroxylpropyl cellulose, hydroxylpropylmethylcellulose, hydroxyethyl cellulose, and methylcellulose cellulose;and non-cellulosic thermoplastic polymers comprise, but not limited to,polyvinyl pyrrolidone, polyvinyl acetate polyvinyl alcohol, butyl/methylmethacrylate-dimethylaminoethylmethacrylate copolymer, polyethyleneglycol, polyethylene oxide, polypropylene glycol and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol.

In one embodiment, the thermo-formable matrix comprises at leasthydroxypropyl cellulose wherein the molecular weight is from 80,000g/mol to 1,150,000 g/mol.

In another embodiment, the thermo-formable matrix comprises at leastpolyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer,wherein the molecular weight is 118,000 g/mol.

The yet another embodiment, the thermo-formable matrix comprises one ormore substrates, including polyelectrolytes, inorganic adsorbents,inclusion compounds and fatty acids.

In one aspect, substrates comprising polyelectrolytes are selected, forexample, from the group consisting of nucleic acids, poly (L-lysine),poly (L-glutamic acid), carrageenan, alginates, and hyaluronic acid,pectin, chitosan (deacetylation of chitin), cellulose-based,starch-based and dextran-based polymers poly(vinylbenzyl trialkylammonium), poly(4-vinyl-N-alkyl-pyridimiun),poly(acryloyl-oxyalkyl-trialkyl ammonium), poly(acryamido-alkyl-trialkylammonium), poly(diallydimethyl-ammonium), poly(acrylic or methacrylicacid), and poly(itaconic acid) and maleic acid/diallyamine copolymer,crosslinked copolymers such as carbopols, crosscarmellose, ion exchangeresins and mixtures thereof.

Examples of ion exchange resins include sulfonated copolymer of styreneand divinylbenzene, a carboxylate copolymer of styrene anddivinylbenzene, a copolymer of styrene and divinylbenzene containingquaternary ammonium groups such as Amberlite® IR-120, Amberlite® XE-69,Amberlite® IRP-64/69, Dowex® 50WX2, Dowex® 50WX4, Dowex® 50WX8, fDuolite® AP 143, Indion® 204, Indion® 214, Indion® 234, Indion® 264,Tulsion® 335, Tulsion® 339, and Tulsion® 343 and mixtures thereof.

In another aspect, substrates comprising inorganic adsorbents areselected, for example, from the group consisting of but not limited toaluminum silicate, attapulgite, bentonite, calcium silicate, kaolin,lithium magnesium aluminum silicate, lithium magnesium silicate, lithiummagnesium sodium silicate, magnesium silicate, magnesium trisilicate,montmorillonite, pyrophyllite, sodium magnesium silicate, zeolite, andzirconium silicate and mixtures thereof.

In yet another aspect, substrates comprising inclusion compounds areselected, for example, from the group consisting of but not limited toα-cyclodextrins, β-cyclodextrins and γ-cyclodextrins.

In yet another aspect, substrates comprising fatty acids are selectedfrom the group, for example, consisting of but not limited toarachidonic acid, capric acid, caprylic acid, dihomo-γ-linoleic acid,docesenoic acid, docosatetraenoic acid, docosohexaconic acid,docosopentanoic acid, eicosapentanoic acid, gondoic acid, lauric acid,linoleic acid, α-linoleic acid, 6-linoleic acid, myristic acid, nervonicacid, oleic acid, oleostearic acid, palmitic acid, palmitoleic acid,stearic acid, and vaccenic acid and mixtures thereof.

In another embodiment, the thermo-formable matrix comprises prodrugsconsisting of, for example, from the group but not limited to amides andesters of therapeutic agents.

In another embodiment, the thermo-formable matrix comprisespharmaceutical additives consisting of plasticizers, waxes, surfactants,inorganic fillers, anti-adherents, erosion enhancers, and optionally,stabilizers.

Examples of plasticizers include, but not limited to, dibutyl sebacate,glycerol, polyethylene glycol, propylene glycol, triacetin, tributylcitrate, and triethyl citrate and mixtures thereof.

Examples of waxes include, but not limited to, bees wax, candilila wax,carnuba wax, and paraffin wax and mixtures thereof.

Examples of surfactants include, but not limited to, alkyl benzenesulfones, alkyl sulfates, ether carboxylates, glycerol/propylene glycolfatty acid esters, hexadecyl triammonium bromide, hydroxylated lecithin,lauryl carnitine, lower alcohol-fatty acid esters, mono-/di-glycerides,Ovothin®, polyethylene glycol alkyl ethers, polyethylene glycol-fattyacid monoesters, polyethylene glycol-fatty acid diesters, polyethyleneglycol-glycerol esters, polyethylene glycol phenols, polyethyleneglycol-sorbitan fatty acid esters, polyglyceride fatty acids,polyoxyethylene-polyoxypropylene block copolymers, propyleneglycol-fatty acid esters, sodium cholate, sodium lauryl sulfate, sodiumpalmitate, sodium taurocholate, sorbitan-fatty acid esters, sterol andsterol derivatives, sugar esters, transesterification products of oilsand alcohols and mixtures thereof.

Examples of inorganic fillers include, but not limited to silicondioxide, aluminum silicate, attapulgite, bentonite, calcium silicate,calcium carbonate, dicalcium phosphate, kaolin, lithium magnesiumaluminum silicate, lithium magnesium silicate, lithium magnesium sodiumsilicate, magnesium silicate, magnesium trisilicate, montmorillonite,pyrophyllite, sodium magnesium silicate, talc, titanium dioxide,zeolite, and zirconium silicate, and mixtures thereof.

Examples of anti-adherents include, but not limited to, calciumcarbonate, dicalcium phosphate, kaolin, talc, and titanium dioxide, andmixtures thereof.

Examples of erosion enhancers include, but not limited to, hydroxyethylcellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone;mannitol, malitol, sorbitol, xylytol, sodium lauryl sulfate, Chremophorand Polysorbate 80, and mixtures thereof.

Examples of stabilizers include, but not limited to,butylhydroxytoulene, butylhydroxyanisole, propyl gallate, ascorbic acid,vitamin E-TPGS, phosphates, citrates, acetates, oxides and carbonates,and mixtures thereof.

In another embodiment, the tamper-resistant dosage form comprisestherapeutic agents that are susceptible to abuse, i.e. “abuse-prone”,and those that are not.

In one aspect, abuse-prone therapeutic agents comprise, but not limitedto, alfenatil, allylprodine, alphaprodine, anileridine, apomorphine,apocodeine, benzylmorphine, benzitramide, buprenorphine, butorphanol,clonitrazene, codeine, codeine methylbromide, codeine phosphate, codeinesulfate, cyclazocine, cyclorphen, cyprenorphine, desmorphine,dextromethorphan, dextromoramide, dezocine, diamromide, dihydrocodeine,dihydrocodeinone, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, hydrocodone, hydrocodone barbiturate, hydroxymethylmorphinan,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, methylmorphine, metopon, morphine,morphine derivatives, myrophine, nalbuphine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, normorphine, norpipanol,ohmefentanyl, opium, oxycodone, oxymorphone, papaverum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, pheoperidine,pholcodine, piminodine, piritramide, propheptazine, promedol, profadol,properidine, propiram, propoxyphene, remifentanyl, sufentanyl, tramadol,tilidine, naltrexone, naloxone, nalmefene, methylnaltrexone, naloxonemethiodide, naloxonazine, trindole, naltrindole isothiocyanate,naltriben, norbinaltorphimine, funaltrexmine, and salts or esters of anyof the opioids, acecabromal, bomisovalum, capruide, cabromal, ectylurea,chlorhexadol, ethcholorvynol, meparfynol, 4-methyl-5-thiazolethanol,tetrapentylalcohol, butoctamide, diethylbromoacetamide, ibrotamide,isovarleryl diethylamide, niaprazine, triacetamide, trimetozine,zolpidem, zopiclone; barbituric acid derivatives such as allobarbital,amobarbital, aprobarbital, barbital, brallabarbital, butabarbitalsodium, butabarbital, butallylonal, buthetal, carbubarb, cyclobarbital,cyclopentobarbital, enallylpropymal, 5-ethyl-5-(1-piperidyl)barbituricacid, 5-furfuryl-5-isopropylbarbituric acid, heptabarbital, hexethalsodium, hexobarbital, mephobarbital, methitural, narcobarbital,nealbarbital, pentobarbital sodium, phenallylmal, phenobarbital,phenobarbital sodium, phenylmethylbarbituric acid, probarbital,propallylonal, proxibarbal, reposal, secobarbital sodium, thiopental,talbutal, tetrabarbital, thiobarbital, thiamylal, vinbarbital sodium,and vinylbital, benzodiazepine derivatives such as alprazolam,brotizolam, clorazepate, chlordiazepoxide, clonazepam, diazepam,doxefazepam, estazolam, flunitrazepam, flurazepam, haloxazolam,lorazepam, loprazolam, lormetazepam, nitrazepam, quazepam, temazepam,and triazolam; carbamates such as amylcarbamate, ethinamate,hexaprypymate, meparfynol carbamate, novonal and trichlorourethan;chloral derivatives such as carbocloral, chloral betaine, chloralformamide, chloral hydrate, chloralantipyrine, dichloralphenazone,pentaerithriol chloral and tricloflos; piperidinediones such asgluthemide, methylprylon, piperidione, taglutimide, thalidomide;quinazolone derivatives such as etaqualone, mecloquanone, andmethaqualone; and others such as acetal, acetophenone, aldol, ammoniumvalerate, amphenidone, d-bornyl-a-bromoisovalerate, d-bornylisovalerate,calcium 2-ethylbutanoate, carfinate, α-chlorolose, clomethiazole,cypripedium, doxylamine, etodroxizine, etomidate, fenadiazole,homofenazine, hydrobromic acid, mecloxamine, methyl valerate, opium,paraldehyde, perlapine, propiomazine, rimazafone, sodium oxybate,sulfomethylmethane, sulfonmethane, amphethamine, dextroamphethamine,levoamphetamine, methamphetamine, methylphenidate, phenmetrazine,modatinil, avafinil, armodafinil, and ampalimes; cannabinoids such astetrahydro-cannabinol, nabilone; ketamine, tiletamine, dextromethorphan,ibogaine, dixocilpine; anabolic steroids such as androisoxazole,androstenediol, bolandiiol, clostebol, ethylesternol, formyldienolone,4-hydroxy-19-nortestosterone, methandriol, methenolone,methyltrienolone, nandrolone, nandrolone deconate, nandrolonep-hexyloxyphenylpropionate, nandrolone phenpropionate, norbolethone,oxymestrone, pizotyline, quinbolone, stenbolone and trenbolone;anorexics such as aminorex, amphecloral, benzaphetamine,chlorphentermine, clobenzorex, cloforex, clortermine, cyclexedrine,diethylpropion, diphemethoxidine, n-ethylamphetamine, fenbutrazate,fenfluramine, fenproporex, furfurylmethylamphetamine, levophacetoperate,mazindol, mefenorex, metamfeproamone, norpseudoephedrine,phendimetrazine, phendimetrazine trtrate, phentermine,phenylpropanolamine hydrochloride, picilorex, pseudoephedrine,ephedrine, levo-methamphetamine, phenylpropanolamine, propylhexedrineand synephrine.

In another aspect, therapeutic agents that are not susceptible to abusecomprise, but not limited to, atenolol, albendazole, alendronate,alprostadil, allopurinol, amlexanox, anagrelide, aminophylline,alitretinoin, amodiaquine, astemizole, atovaquone, aztreonam,atorvastatin, azlocillin, baclofen, benazepril, benzonatate, bitolterolmesylate, brompheniramine, cabergoline, carisoprodol, celecoxib,cefpiramide, chlorothiazide, chlormezanone, cimetidine, cetirizine,cefotaxime, ciprofloxacin, cephalexin, chloroquine, clomocycline,cyclobenzaprine, cyproheptadine, cyproheptadine, cefmenoxime,cyclophosphamide, ciclopirox, cladribine, chlorpheniramine,chlorzoxazone, clemastine, clofarabine, cytarabine, dacarbazine,dantrolene, daunorubicin, dexamethasone, diclofenac, diethylcarbamazine,diphenhydramine, diphenylpyraline, disopyramide, diltiazem, dopamine,dofetilide, doxazosin, enoxacin, epirubicin, eplerenone, erlotinib,ertapenem, etoposide, exemestane, ezetimibe, fexofenadine,flucloxacillin, fulvestrant, fenofibrate, fenoprofen, fenoldopam,fluocinonide, flunisolide, fluorouracil, gefitinib, gemcitabine,grepafloxacin, guaifenesin, halofantrine, ibuprofen, ibandronate,ipratropium, irinotecan, isosorbide mononitrate, ipratropium,ivermectin, ketoconazole, ketoprofen, ketorolac, levamisole, letrozole,levosimendan, levofloxacin, lovastatin, loratadine, lymecycline,loracarbef, lisuride, meclofenamate, mefloquine, meloxicam,methocarbamol, methylbromide, metolazone, methyldopa, methdilazine,mequitazine, mitotane, mivacurium, moxifloxacin, mometasone, midodrine,milrinone, nabumetone, naproxen, nifedipine, nilutamide, nedocromil,omeprazole, olmesartan, oxaliplatin, oxamniquine; orphenadrine,pantoprazole, pefloxacin, pentamidine, penicillamine, pemetrexed,perhexiline, phenylbutazone, pipobroman, piroxicam, propranolol,phentermine, phentolamine, piperacillin, piperazine, primaquine,piroxicam, pivoxil, praziquantel, probenecid, porfimer, propafenone,prednisolone, proguanil, pyrimethamine, quinine, quinidine, ranolazine,remikiren, rofecoxib, salmeterol, sulfanilamide, sulfadiazine, suprofen,sulfinpyrazone, tenoxicam, triamterene, tolmetin, toremifene,tolazoline, tamoxifen, teniposide, theophylline, terbutaline,terfenadine, thioguanine, tolmetin, trimetrexate, triprolidine,trovafloxacin, verapamil, valsartan, vinorelbine, valrubicin,vincristine, valdecoxib and mixtures thereof.

Tamper-Resistant Dosage Form Properties:

Tamper-resistance is achieved through a synchronized barrier mechanismcomposed of mechanical, physical and chemical components. According tothe disclosure, hardness and plasticity is imparted onto the dosage formthrough a combination of thermal processing and the incorporation ofuniquely blended water-soluble and water-insoluble polymers and otherpharmaceutical additives in the formulation. As a result, the dosageform does not easily get plasticized during chewing and mastication. Itinstead hydrates, forms a thin gel layer and slowly erodes from thesurface upon chewing or mastication while keeping the core dry and hardwith limited liquid penetration. Similarly, the dosage form resistscrushing, breaking and grinding using commonly used tools and hence doesnot generate fine powders suitable for snorting. Even grinding using acoffee grinder only produces coarse particles that are not suitable forsnorting. Moreover, even if the powders were suitable for snorting,which is not the case; the drug would not be available for absorptionthrough the lining of the nasal cavity due to the complex and the rigidmatrix in the particles.

Drug extraction from the dosage form is eliminated or minimized througha synchronized barrier mechanism. During the extraction process, thethermo-formable matrix generates a thin viscous gel layer on the surfaceover the hard and dry core of the dosage form, the thickness of which isdictated by the type of extraction solvent employed. In all cases,however, the drug-substrate complex present at the solvated gel layercannot diffuse out into the extraction medium due to its poor mobilitywithin the gel layer. Even if the thin gel layer were to erode andreleases the drug-substrate complex into the extraction medium, the drugwhich, is tightly bound to the complex, and in turn “coated” by thethermoplastic polymer from the matrix, does not readily become availablefor extraction. This synchronized barrier mechanism comprising physical,mechanical and chemical components is a feature that differentiates theinvention from prior art.

Abusers often heat the dosage forms to vaporize the drug for smokingpurposes. According to the invention, vaporization of a drug from thedosage form is prevented through density and hardness of the dosageform, immobilization of the drug within the drug-substrate complex, andimmobilization of the drug-substrate complex within the thermo-formablematrix. The drug-substrate complex has much lower vapor pressure thanthat of the free drug, and, as a result, requires much higher heatenergy to liberate the free drug from the complex and the matrix, if thedosage form were thermally stable when exposed to elevated temperatures.However, it was discovered that excessive heating of the dosage formleads to decomposition and charring of formulation components whichpotentially liberate obnoxious fumes that the abuser may not tolerate.

Mechanism of Drug Release:

Without limiting the scope of this invention, the mechanism of how adrug is released from the tamper-resistant dosage form can beillustrated by FIG. 1. According to the invention, the tamper-resistantdosage form and the mechanism of release are applicable to either thetablet or the multiparticulate forms of the drug. As shown in FIG. 1, atablet may be represented by a plurality of drug-substrate (DS)complexes, including prodrugs, imbedded in a matrix.

Under Step 1, the tablet surface undergoes a hydration process thatleads to the formation of a gel layer when a tablet is immersed in adissolution medium or gastrointestinal fluid. Under Step 2, erosion ofthe gel layer takes place, leading to the release of the drug-substrate(DS) complexes. At this stage, the drug-substrate (DS) complexes aredislodged from the tablet and get suspended in the dissolution medium orgastrointestinal fluid. Under Step 3, free drug (D) is released from thedrug-substrate (DS) complexes into the dissolution medium orgastrointestinal fluid through ionic displacement, enzymatic cleavage orpH effect.

According to the invention, drug release from the tamper-resistantdosage form is controlled by (a) hardness of the dosage from whichcontrols the rate of fluid penetration into the core, (b) composition ofthe dosage form which controls the strength, hydration rate anddissolution of the gel layer, and (c) the decomplexation process in thedissolution medium or gastrointestinal fluid. Such control as describedin the present invention ensures that the dosage form would not besusceptible to dose dumping or food effect as is frequently observedwith dosage forms that rely exclusively on matrix control for release.

In one embodiment, the tamper-resistant dosage form according to theinvention is resistant to abuse by chewing. The dosage form cannot bechewed irrespective of the bite force. It only erodes over time. Theeroded material still contains the drug-substrate complex “coated” bythe thermoformable matrix components which would in turn make the drugless available for absorption upon ingestion. Examples of prescriptiondrugs abused by swallowing include; barbiturates such as phenobarbitaland secobarbital; opioids such as morphine, codeine, fentanyl,methadone, oxycodone HCl, hydrocodone bitartrate, hydromorphone,oxymorphone, meperidine, propoxyphene and dextromethorphan;benzodiazepines such as diazepam and clonazepam; sleep medications suchas zolpidem and zaleplon; and stimulants such as amphetamine andmethylphenidate.

In another embodiment, the dosage form according to the invention isresistant to abuse by snorting. Since the dosage form does not getreduced into fine powder, it does not allow the abuser to administer thetherapeutic agent intra-nasally to facilitate drug absorption throughthe lining of the nasal passages by snorting. Even if the dosage fromwere susceptible to produce fine powders upon pulverization, which isnot the case, the therapeutic agent would still be tightly bound to thesubstrate and “coated” by the thermoplastic polymer, and not becomeavailable for intra-nasal absorption. Examples of prescription drugsabused by snorting include: opioids such as morphine, codeine, fentanyl,methadone, oxycodone HCl, hydrocodone bitartrate, hydromorphone,oxymorphone, meperidine and propoxyphene; sleep medications such aszolpidem and zaleplon; stimulants such as amphetamine andmethylphenidate.

In yet another embodiment, the dosage form according to the inventionprevents abuse by injection. Extraction of the therapeutic agent usingcommonly used organic and household solvents with continuous agitationof the dosage form for at least 8 hours in 30 mL or 200 mL extractionvolume leads to insignificant drug release. Similar results wereobtained when the dosage form was milled in a coffee grinder andsimilarly tested for 15 minutes (as shown in FIG. 2A) and 60 minutes (asshown in FIG. 2B). Examples of prescription drugs abused by injectioninclude: barbiturates, such as phenobarbital and secobarbital; opioidssuch as morphine, codeine, fentanyl, methadone, oxycodone HCl,hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine andpropoxyphene; stimulants such as amphetamine and methylphenidate.

In yet another embodiment, the present invention relates to a dosageform that prevents drug abuse by smoking where the therapeutic agentneeds to vaporize for inhalation after exposure of the dosage form toheat. For example, the dosage form is placed on top of a spoon, andheated from underneath using a cigarette lighter or high temperatureacetylene torch to vaporize the therapeutic agent. Excessive heating ofthe dosage form leads to decomposition and charring of formulationcomponents. Examples of prescription drugs abused by smoking include:fentanyl and its analogs, amphetamines, and morphine.

In yet another embodiment, the present invention relates to a dosageform that prevents drug abuse by ingestion of multiple tablets. Theamount of drug released from multiple tablets in simulatedgastrointestinal fluid relative to a single unit is greatly reduced andis not dose proportional. It is expected that the spike desired byabusers would not occur when more units than required by dosinginstructions are ingested by the abusers.

In yet another embodiment, the present invention relates to formulationsthat provide multiple modified release profiles. The profiles, whichrange from over 90% in 4 hours to greater than 90% in 24 hours (FIG. 3),demonstrate the flexibility of the formulations and the opportunity theyprovide during the development of dosage forms that satisfy the diversepharmacokinetic requirements of therapeutic agents.

In yet another embodiment, the present invention relates to a dosageform that generates release rates that are independent of therapeuticagents. That is, different therapeutic agents incorporated in a givenformulation provide the same release profiles. Such a surprisingdiscovery makes it possible to establish base formulations (templates)that would form the basis for the development of different products,thereby shortening development time (FIG. 4).

In yet another embodiment, the present invention relates to a dosageform that increases the shelf life of products by eliminating or atleast minimizing oxidative or hydrolytic decomposition of therapeuticagents. Many therapeutic agents, including opioids, undergo oxidative orhydrolytic degradation when exposed to acidic or alkaline aqueousenvironments or thermal stresses, or both. Moreover, some pharmaceuticaladditives, such as polyethylene oxide, contain trace amounts ofperoxides and promote oxidation of the therapeutic agent upon storage orduring thermal processing, and, as a result, anti-oxidants and bufferingagents are routinely added to formulations to prevent potentialdegradation of therapeutic agents through the shelf-life of the dosageforms. In the present invention, the formation and incorporation of thedrug-substrate complex within the thermo-formable matrix generallyobviates the need for incorporating anti-oxidants and buffering agentsin the dosage form, although incorporation of these agents is alsopossible in special cases.

In yet another embodiment, the invention relates to a tamper-resistantdosage form that ensures dissolution stability and consequently theshelf-life of products. The dissolution stability of matrix-based dosageforms is dictated by the rate of migration of the drug molecules withinthe matrix which in turn depends on the physical stability of the matrixand the properties of the drug substance. Changes in the physicalstability of the matrix retards or accelerates the migration of the drugmolecules, which in turn affect release rate. In contrast, according tothe current invention, mobility of the drug-substrate complex isrestricted within the matrix, thereby enhancing dissolution stability ofthe dosage form.

In yet another embodiment, the invention relates a tamper-resistantdosage form comprising multi-particulates that are compressed intotablets and release the therapeutic agent from less than an hour up to24 hours (FIG. 5). Multiparticulates are blended with other tabletingexcipients and compressed prior to dissolution testing. Duringdissolution, the compressed tablets disintegrate in less than a minuteto regenerate the original multiparticulates which control the releaserate.

EXAMPLES

The following examples are included to demonstrate certain embodimentsof the present invention and not intended to be limiting. They are forillustrative purposes only and it is to be noted that changes andvariations can be made without departing from the spirit and scope ofthe invention.

Example 1 Preparation of Drug-Substrate Complex

In this example, a general process for the preparation of adrug-substrate complex is illustrated using an ion exchange resin as amodel substrate. For example, a drug-ion exchange resin complex isprepared from a blend of the drug and Amberlite IRP 69 (Sodiumpolystyrene sulfonate, manufactured by Rohm Haas, Philadelphia, Pa., USAand supplied by Dow Chemical Company, Midland, Mich., USA) using a novelreactive extrusion process. A 16 mm twin-screw extruder is used as areactor, although larger size extruders could be used if the desiredbatch size is high. The drug and Amberlite IRP 69 are pre-blended andthe blend introduced into the extruder through a powder feed port. At asecond port downstream from the first feed port, deionized water isadded at a controlled rate to generate a heavy suspension. The extrusionprocess is carried out at a screw speed of 300 rpm and processingtemperatures of 25° C. The suspension is collected, dried in a dryingoven and stored for further processing.

Alternatively, the suspension is washed using deionized water to removeany free uncomplexed drug as is done with other methods known in theart. The supernatant is decanted and discarded. The residue comprising adrug-ion exchange resin complex is then dried in a drying oven.

Example 2 Propranolol Ion-Exchange Resin Complex Particles

A formulation composed of a complex of a therapeutic agent(propranolol), and a substrate (ion-exchange resin) only, without theincorporation of a thermoplastic polymer, and hence a thermoformablematrix, was prepared. The propranolol ion exchange resin complex wasprepared using the procedure described in Example 1.

Dissolution Studies:

Dissolution studies were conducted in 900 mL of pH 6.8 Phosphate buffer(0.05M) consisting of 0.2% sodium chloride using USP Apparatus II(Paddle) at 75 rpm. The dissolution data is given below:

Time % (h) Released 0.25 78 0.5 89 1 96 2 98

Extraction Studies

Extraction studies were conducted in different solvents using a wristaction shaker at a speed of 416 rpm and 18° angle. Samples werewithdrawn at 15 minutes and 60 minutes and the drug release wasdetermined using a spectrophotometer. The results are given below:

% Released Extraction 15 60 Solvent min min 0.9% NaCl 3.4 3.6 solutionMethanol 0.4 0.5 Water 0.5 0.4 0.1N HCl 1.4 1.4 Ethanol 40% 0.4 0.4 0.1NNaOH 2.7 2.5 Ethanol 96% 0.2 0.2 Isopropanol 0.6 0.8 Ethylacetate 0.20.2

Example 3 Propranolol HCl Multiparticulates

A formulation composed of a therapeutic agent (propranolol),thermoplastic polymers (hydroxypropylcellulose I and II) and apharmaceutical additive (silicon dioxide) was prepared. Neither asubstrate, nor a therapeutic agent-substrate complex was included in theformulation.

Propranolol HCl (free drug), hydroxypropylcellulose (I),hydroxypropylcellulose (II) and silicon dioxide were blended, fed into a16 mm twin screw extruder and extruded. The extrusion process wascarried out at a processing temperature of 140° C. and a screw speed of200 rpm. The extrudates were shaped into multiparticulates downstream. Aportion of the multiparticulates were mixed with external excipients andcompressed into tablets. The tablets and the remaining portion ofmultiparticulates were collected and stored in high density polyethylene(HDPE) bottles.

% Ingredient w/w Propranolol HCl 25 Hydroxypropyl cellulose (I) 35.5(M.W. 370,000) Hydroxypropyl cellulose (II) 35.5 (M.W. 80,000) Silicondioxide 4 Total 100

Dissolution Studies:

Dissolution studies were conducted in pH 6.8 Phosphate buffer (0.05M)consisting of 0.2% sodium chloride using USP Apparatus II (Paddle) at 75rpm. The tablets disintegrated within 1 minute in the dissolutionmedium. The dissolution data is given below:

Time % (h) Released 0.25 41 0.5 69 1 100

Extraction Studies

Extraction studies were conducted in different solvents using a wristaction shaker at a speed of 416 rpm and 18° angle. Samples werewithdrawn at 15 minutes and 60 minutes and drug release determined usinga spectrophotometer. The results are given below:

% Released Extraction 15 60 Solvent min min 0.9% NaCl 62.6 94.2 solutionMethanol 94.7 99.3 Water 77.4 94.2 0.1N HCl 68.7 90.8 Ethanol 40% 42.485.9 0.1N NaOH 4.3 5.0 Ethanol 96% 42.8 80.7 Isopropanol 22.5 44.1Ethylacetate 23.4 25.4

Example 4 Propranolol HCl and Ion-Exchange Resin Blend-BasedMultiparticulates

A formulation composed of a therapeutic agent (propranolol), a substrate(Amberlite IRP 69), thermoplastic polymers (hydroxypropylcellulose I andII) and a pharmaceutical additive (silicon dioxide) was prepared. Thetherapeutic agent and the substrate were incorporated in the formulationindependently and not as a pre-formed complex.

Propranolol HCl (free drug), Amberlite IRP 69 (uncomplexed resin),hydroxypropylcellulose (I), hydroxypropylcellulose (II) and silicondioxide were blended, fed into a 16 mm twin screw extruder and extruded.The extrusion process was carried out at processing temperatures of 140°C. and a screw speed of 200 rpm. The extrudates were shaped intomultiparticulates downstream. A portion of the multiparticulates weremixed with external excipients and compressed into tablets. The tabletsand the remaining portion of the multiparticulates were collected andstored in high density polyethylene (HDPE) bottles.

% Ingredient w/w Propranolol HCl 25 Amberlite IRP 69 (Ion-exchange 25resin) Hydroxypropyl cellulose (I) 23 (M.W. 370,000) Hydroxypropylcellulose (II) 23 (M.W. 80,000) Silicon dioxide 4 Total 100

Dissolution Studies:

Dissolution studies were conducted in pH 6.8 Phosphate buffer (0.05M)consisting of 0.2% sodium chloride using USP Apparatus II (Paddle) at 75rpm. The tablets disintegrated within 1 minute in the dissolutionmedium. The dissolution data is given below:

Time % (h) Released 0.25 43 0.5 63 1 93 2 100

Extraction Studies

Extraction studies were conducted on the multiparticulates in differentsolvents using a wrist action shaker at a speed of 416 rpm and 18°angle. Samples were withdrawn at 15 minutes and 60 minutes and the drugrelease was determined using a spectrophotometer. The results are givenbelow:

% Released Extraction 15 60 Solvent min min 0.9% NaCl 45.6 58.3 solutionMethanol 75.4 77.6 Water 54.5 57.2 0.1N HCl 41.2 40.6 Ethanol 40% 44.645.1 0.1N NaOH 5.7 5.4 Ethanol 96% 64.8 69.5 Isopropanol 36.4 55.2Ethylacetate 9.3 12.3

Example 5 Propranolol Ion-Exchange Resin Complex-Based Multiparticulates

A formulation composed of a therapeutic agent-substrate complex(Propranolol-Amberlite IRP 69 complex), thermoplastic polymers(hydroxypropylcellulose I and II) and a pharmaceutical additive (silicondioxide) was prepared.

Propranolol ion exchange complex, hydroxypropylcellulose (I),hydroxypropylcellulose (II) and silicon dioxide were blended, fed into a16 mm twin screw extruder and extruded. The extrusion process wascarried out at a processing temperature of 140° C. and a screw speed of200 rpm. The extrudates were shaped into multiparticulates downstream. Aportion of the multiparticulates were mixed with external excipients andcompressed into tablets. The tablets and the remaining portion ofmultiparticulates were collected and stored in high density polyethylene(HDPE) bottles.

% Ingredient w/w Propranolol Ion Exchange 50 Resin Complex Hydroxypropylcellulose (I) 23 (M.W. 370,000) Hydroxypropyl cellulose (II) 23 (M.W.80,000) Silicon dioxide 4 Total 100

Dissolution Studies:

Dissolution studies were conducted in pH 6.8 Phosphate buffer (0.05M)consisting of 0.2% sodium chloride using USP Apparatus II (Paddle) at 75rpm. The tablets disintegrated within 1 minute in the dissolutionmedium. The dissolution data is given below:

Time % (h) Released 0.25 0.5 0.5 4 1 13 2 35 3 62 4 77

Extraction Studies

Extraction studies were conducted in different solvents using a wristaction shaker at a speed of 416 rpm and 18° angle. Samples werewithdrawn at 15 minutes and 60 minutes and the drug release wasdetermined using a spectrophotometer. The results are given below:

% Released Extraction 15 60 Solvent min min 0.9% NaCl 3.1 4.5 solutionMethanol 2.3 2.6 Water 0.9 3.4 0.1N HCl 1.5 2.1 Ethanol 40% 1.0 1.1 0.1NNaOH 5.5 5.7 Ethanol 96% 1.9 5.0 Isopropanol 1.0 2.5 Ethylacetate 0.71.2

Example 6 Dextromethorphan-Ion Exchange Resin Complex-Based Tablets

A mixture of Dextromethorphan ion exchange resin complex,hydroxypropylcellulose (I), hydroxypropylcellulose (II) and polyethyleneglycol were blended and fed into a 16 mm twin screw extruder andextruded at extrusion temperatures of 100° C. and a screw speed of 200rpm. The extrudate was shaped into tablets downstream. The tablets werecollected and stored in high density polyethylene (HDPE) bottles.

% Ingredient w/w Dextromethorphan Ion Exchange Resin 50 ComplexHydroxypropyl cellulose (I) (M.W. 26.25 370,000) Hydroxypropylcellulose(II) (M.W. 8.75 80,000) Polyethylene glycol (M.W. 400) 15 Total 100

Dissolution Studies:

Dissolution studies were conducted in pH 6.8 Phosphate buffer (0.05M)consisting of 0.2% sodium chloride using USP Apparatus I (basket) at 100rpm. The dissolution data is given below:

Time % (h) Released 1 7 2 15 3 21 4 28 5 34 6 40 7 45 8 49

Extraction Studies

Extraction studies were conducted in different solvents using a wristaction shaker at a speed of 416 rpm and 18° angle. Samples werewithdrawn at 15 minutes and 60 minutes, and the drug release wasdetermined using a UV-spectrophotometer. The results are given below:

Intact Tablets % Released Extraction 15 60 Solvent min min Methanol 1.22.3 Water 0.2 0.3 0.1N HCl 1.7 2.7 Ethanol40% 0.5 0.7 0.1N NaOH 6.9 6.2Ethanol 96% 0.7 1.5 Isopropanol 0.3 0.6 Ethylacetate 0.3 0.7

Example 7 Propranolol Tablet Formulations Manufactured by DryGranulation

A mixture of Propranolol ion exchange resin complex, hydroxypropylmethyl cellulose K100M CR (I), Lactose, PVP K30 and stearic acid wereblended, dry granulated, milled and compressed. Tablets were collectedand stored in high density polyethylene (HDPE) bottles.

% Ingredient w/w Propranolol Ion Exchange Resin 50 ComplexHydroxypropylmethyl cellulose 30 K100 M CR Lactose 10 PVP K30 9.5Stearic acid 0.5 Total 100

Dissolution Studies:

Dissolution studies were conducted using USP Apparatus II (Paddle) at100 rpm in pH 6.8 Phosphate buffer (0.05M) consisting of 0.2% sodiumchloride. The dissolution data is given below

Time % (h) Released 0 0 1 11 2 20 3 27 4 33 5 38 6 45 7 51 8 56

Extraction studies were conducted in different solvents using a wristaction shaker at a speed of 416 rpm and 18° angle. Samples werewithdrawn at 15 minutes and 60 minutes and the drug release wasdetermined using a spectrophotometer. The results are given below:

% Released Extraction 15 60 Solvent min min Methanol 3.0 3.2 0.1N HCl2.9 3.1 0.1N NaOH 6.7 8.0 Ethylacetate 1.1 1.8

Example 8 Propranolol Tablet Formulations Manufactured by WetGranulation

A mixture of Propranolol ion exchange resin complex, hydroxypropylmethylcellulose LVCR CR (I), and Polyethylen oxide, PVP K30 were blended andwet granulated. The granulation was dried in forced air oven at 40° C.overnight and delumped by passing through a screen. The milledgranulation was then compressed in to appropriate tablet size. Tabletswere collected and stored in high density polyethylene (HDPE) bottles.

% Ingredient w/w Propranolol Ion Exchange Resin 50 ComplexHydroxypropylmethyl cellulose LV CR 40 Polyethylenoxide (M.W. 200,000)10 Total 100

Dissolution Studies:

Dissolution studies were conducted using USP Apparatus II (Paddle) at100 rpm in pH 6.8 Phosphate buffer (0.05M) consisting of 0.2% sodiumchloride. The dissolution data is given below:

Time % (h) Released 0 0 1 6 2 14 3 22 4 31 5 44 6 55 7 71 8 82

Extraction studies were conducted in different solvents using a wristaction shaker at a speed of 416 rpm and 18° angle. Samples werewithdrawn at 15 minutes and 60 minutes and the drug release wasdetermined using a spectrophotometer. The results are given below:

% Released Extraction 15 60 Solvent min min Methanol 8.2 9.5 0.1N HCl3.5 4.4 0.1N NaOH 7.9 15.4 Ethylacetate 2.2 3.2

Examples 2-4 demonstrate that a pre-formed therapeutic agent-substratecomplex embedded into the hard, erodible, thermo-formable matrix iscritical to generate a dosage form that is tamper-resistant and providesprogrammed extended release profiles. Examples 5 and 6 show that targetdissolution profiles and tamper-resistance can be achieved whether thedosage form comprises tablets or multiparticulates, very surprisingresults not taught in the prior art. Examples 7 and 8 demonstrate that avariety of dissolution profiles with excellent tamper-resistance can beobtained consistently by a dry granulation process or a wet granulationprocess as long as the therapeutic agent-substrate complex is embeddedwithin the thermo-formable matrix.

What is claimed is:
 1. A tamper resistant dosage form composition,comprising: a therapeutic agent-substrate complex prepared by anextrusion process.
 2. The dosage form of claim 1, wherein the weightratio of the therapeutic agent to substrate of the therapeuticagent-substrate complex is from between 1:20 and 20:1.
 3. A tamperresistant dosage form composition, comprising a therapeuticagent-substrate complex; said therapeutic agent-substrate complex isembedded in an erodible thermo-formable matrix prepared by a granulationprocess.
 4. The dosage form of claim 3, wherein the weight ratio of thetherapeutic agent-substrate complex to the erodible thermo-formablematrix is from between 1:10 to 10:1.
 5. The dosage form of claim 3,wherein the therapeutic agent-substrate and a free substrate is embeddedin the erodible thermo-formable by the granulation process.
 6. Thetamper resistant dosage form composition, comprising an erodiblethermo-formable matrix comprising at least one cellulosic thermoplasticpolymer and optionally at least one non-cellulosic thermoplastic polymerand at least one pharmaceutical additive.
 7. The tamper resistant dosageform of claim 6, wherein the amount of the pharmaceutical additives inthe thermo-formable matrix is less than 20% by weight.
 8. The tamperresistant dosage form composition, comprising: monolithic tablets andmultiparticulates comprising a therapeutic agent-substrate complexembedded in an erodible thermo-formable matrix, wherein the dosage formis resistant to tampering through a synchronized barrier mechanism. 9.The tamper resistant dosage form composition, comprising: monolithictablets and multiparticulates comprising a therapeutic agent-substratecomplex embedded in an erodible thermo-formable matrix, wherein therelease mechanism eliminates or reduces the effect of intentional orunintentional dosing of multiple tablets.
 10. The tamper resistantdosage form composition, comprising: monolithic tablets andmultiparticulates comprising a therapeutic agent-substrate embedded inan erodible thermo-formable matrix, wherein said dosage forms comprisedrug independent template formulations.
 11. The tamper resistant dosageform composition, comprising: monolithic tablets and multiparticulatescomprising a therapeutic agent-substrate complex embedded in an erodiblethermo-formable matrix wherein the formulations impart physical andchemical stability on to dosage form.
 12. The tamper resistant dosageform composition, comprising: monolithic tablets and multiparticulatescomprising a therapeutic agent-substrate complex embedded in an erodiblethermo-formable matrix wherein the release profiles extend from one hourto 24 hours.
 13. The dosage form in claim 1 wherein the extrusionprocess comprises a reactive extrusion process wherein the therapeuticagent and the substrate interact to form the complex.
 14. The dosageform in claim 13 wherein the substrate has an average particle sizedistribution is from 5 u up to 250 u.
 15. The dosage form in claim 3wherein the granulation process comprises melt granulation, wetgranulation and dry granulation.
 16. The dosage form in claim 6 whereinthe cellulosic thermoplastic polymer comprises hydroxylpropyl cellulose,hydroxylpropyl methylcellulose, hydroxyethyl cellulose, andmethylcellulose.
 17. The dosage form in claim 6 wherein thenon-cellulosic thermoplastic polymer comprises polyvinyl pyrrolidone,polyvinyl acetate polyvinyl alcohol, butyl/methylmethacrylate-dimethylaminoethylmethacrylate copolymer, polyethyleneglycol, polyethylene oxide, polypropylene glycol and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol.
 18. The dosage formin claim 6 wherein the at least one pharmaceutical additives areselected from the group consisting of a plasticizer, a wax, asurfactant, inorganic filler, an anti-adherent, an erosion enhancer, astabilizer, and mixtures thereof.
 19. The dosage form in claim 1 furthercomprising a synchronized barrier mechanism comprising physical,mechanical and chemical components.
 20. The dosage form in claim 20wherein the synchronized barrier provides resistance to chewing,crushing, milling, extraction or vaporization.
 21. The dosage form inclaim 19 wherein the synchronized barrier prevents drug abuse byswallowing, snorting, injection or smoking.
 22. The dosage form in claim1 wherein a release mechanism reduces or eliminates the undesirableeffects of swallowing multiple dosage forms in a manner not intended bythe dosing instructions.
 23. The dosage form in claim 1 wherein a drugindependent template formulations comprise formulations that permitsubstitution of one therapeutic agent for another without alteringdissolution profiles and tampering properties.
 24. The dosage form inclaim 3, wherein physical and chemical stability of the therapeuticagent and physical stability of the matrix is achieved by a combinationof the therapeutic agent-substrate complex and the rigid, erodiblethermo-formable matrix.
 25. The dosage form in claim 1, wherein thetablets release the therapeutic agent in 4 to 24 hours.
 26. The dosageform in claim 1, wherein the multiparticulates release the therapeuticagent in 1 to 24 hours.
 27. The dosage form in claim 1 wherein thetherapeutic agent is selected from the group consisting of morphine,hydromorphone, oxymorphone, codeine, hydrocodone oxycodone, pentazocine,naloxone, noltrexone, alprazolam, zopiclone, amphetamine,methylphenidate, dextromethorphan, ephedrine, pseudoephedrine,chlorpheniramine, propranolol, verapamil, clonidine, albuterol andacceptable salts thereof.
 28. The dosage form in claim 1 wherein thesubstrate is selected from the group consisting of a polyelectrolyte, afatty acid, an inorganic adsorbent and an inclusion compound.
 29. Thedosage form in claim 1 wherein reactive extrusion is carried out in atwin screw extruder under controlled conditions of temperature, pressureand pH.
 30. The dosage form in claim 3, wherein the melt granulation iscarried out in a twin screw extruder at processing temperatures below150° C.
 31. The dosage form in claim 28 wherein the polyelectrolyte isselected from the group consisting of nucleic acids, poly (L-lysine),poly (L-glutamic acid), carrageenan, alginates, hyaluronic acid, pectin,chitosan (deacetylation of chitin), cellulose-based, starch-based,dextran-based polymers, poly (vinylbenzyl trialkyl ammonium), poly(4-vinyl-N-alkyl-pyridimiun), poly (acryloyl-oxyalkyl-trialkylammonium), poly (acryamidoalkyl-trialkyl ammonium), poly(diallydimethyl-ammonium), poly (acrylic or methacrylic acid), and poly(itaconic acid) and maleic acid/diallyamine copolymer, carbopols,crosscarmellose, and ion exchange resin.
 32. The dosage form in claim 30wherein the ion exchange resin is selected from the group consisting ofa sulfonated copolymer of styrene and divinylbenzene, a carboxylatecopolymer of styrene and divinylbenzene, a copolymer of styrene anddivinylbenzene containing quaternary ammonium groups.
 33. The dosageform in claim 28 wherein the fatty acid is selected from the groupconsisting of arachidonic acid, capric acid, caprylic acid,dihomo-γ-linoleic acid, docesenoic acid, docosatetraenoic acid,docosohexaconic acid, docosopentanoic acid, eicosapentanoic acid,gondoic acid, lauric acid, linoleic acid, α-linoleic acid, 6-linoleicacid, myristic acid, nervonic acid, oleic acid, oleostearic acid,palmitic acid, palmitoleic acid, stearic acid, vaccenic acid andmixtures thereof.
 34. The dosage form in claim 28 wherein the inorganicadsorbent is selected from the group consisting of silicon dioxide,aluminum silicate, attapulgite, bentonite, calcium silicate, kaolin,lithium magnesium aluminum silicate, lithium magnesium silicate, lithiummagnesium sodium silicate, magnesium silicate, magnesium trisilicate,montmorillonite, pyrophyllite, sodium magnesium silicate, zeolite, andzirconium silicate and mixtures thereof.
 35. The dosage form in claim 28wherein the inclusion compound is selected from the group consisting ofα-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.
 36. The dosage formin claim 18, wherein the plasticizer is selected from the groupconsisting of dibutyl sebacate, glycerol, polyethylene glycol, propyleneglycol, triacetin, tributyl citrate, and triethyl citrate and mixturesthereof.
 37. The dosage form in claim 18, wherein the wax is selectedfrom the group consisting of bee's wax, candilila wax, carnuba wax, andparaffin wax and mixtures thereof.
 38. The dosage form in claim 18,wherein the surfactant is selected from the group consisting of alkylbenzene sulfones, alkyl sulfates, ether carboxylates, glycerol/propyleneglycol fatty acid esters, hexadecyl triammonium bromide, hydroxylatedlecithin, lauryl carnitine, lower alcohol-fatty acid esters,mono-/di-glycerides, Ovothin®, polyethylene glycol alkyl ethers,polyethylene glycol-fatty acid monoesters, polyethylene glycol-glycerolesters, polyethylene glycol phenols, polyethylene glycol-sorbitan fattyacid esters, polyglyceride fatty acids, polyoxyethylene-polyoxypropyleneblock copolymers, propylene glycol-fatty acid esters, sodium cholate,sodium lauryl sulfate, sodium palmitate, sodium taurocholate,sorbitan-fatty acid esters, sterol and sterol derivatives, sugar esters,and mixtures thereof.
 39. The dosage form in claim 18, wherein theinorganic fillers is selected from the group consisting of aluminumsilicate, attapulgite, bentonite, calcium silicate, kaolin, lithiummagnesium aluminum silicate, lithium magnesium silicate, lithiummagnesium sodium silicate, magnesium silicate, magnesium trisilicate,montmorillonite, pyrophyllite, sodium magnesium silicate, zeolite, andzirconium silicate and mixtures thereof.
 40. The dosage form in claim18, wherein the anti-adherent is selected from the group consisting ofcalcium carbonate, dicalcium phosphate, kaolin, talc, and titaniumdioxide, and mixtures thereof.
 41. The dosage form in claim 18, whereinthe erosion enhancer is selected from the group consisting ofhydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethyleneoxide, polyvinyl pyrollidone, mannitol, malitol, sorbitol, xylitol,lactose, sodium lauryl sulfate, Polysorbate 80, and chremophor andmixtures thereof.
 42. The dosage form in claim 18, wherein thestabilizer is selected from the group consisting of butylhydroxytoulene,butylhydroxyanisole, propyl gallate, ascorbic acid, vitamin E-TPGS,phosphates, citrates, acetates, oxides, carbonates and mixtures thereof.43. A process for making a tamper resistant dosage form; the processcomprising: (1) blending at least one therapeutic agent and at least onesubstrate in a therapeutic agent-to-substrate ratio between 1:20 to 20:1by weight; (2) reacting the at least one therapeutic agent and the atleast one substrate to form a therapeutic agent-substrate complex; (3)forming a thermo-formable matrix blend with at least one thermoplasticpolymer and optionally at least one pharmaceutical additive; (4) mixingthe therapeutic agent-substrate complex and the thermo-formable matrixblend in a ratio between 1:10 to 10:1 by weight; (5) granulating thetherapeutic agent-substrate complex and the thermo-formable matrix blendto form the tamper-resistant dosage form in which the therapeuticagent-substrate complex is embedded in the thermo-formable matrix; and(6) shaping the tamper-resistant dosage form into a tablet andmultiparticulates.